Gene mutation in hereditary progressive dystonia with marked diurnal fluctuation (HPD), strictly defined dopa-responsive dystonia

Mutations of the guanosine triphosphate (GTP)-cyclohydrolase I (GCH-I) gene, which catalyzes the first step in the tetrahydrobiopterin (the natural cofactor for tyrosine hydroxylase) biosynthesis, are demonstrated to cause HPD, i.e. strictly defined dopa-responsive dystonia. We analyzed the GCH-I gene of patients who fulfilled clinical criteria for typical hereditary progressive dystonia (HPD) to finalize the diagnosis. Two novel point mutations in two independent families and one novel de novo point mutation in one sporadic patient were identified. In a Japanese family, a T-to-C transition was found at exon 2, which resulted in a substitution of Cys 141 to Arg. In another Japanese family, a C-to-T mutation in exon 4 caused a nonsense codon Gln180Stop. In a clinically sporadic Japanese patient, T-to-G transition in exon 1 brought Met 102 Arg missense mutation, which was not observed in its biological parents. These three mutations were not observed in previously reported 57 pedigrees/patients and no polymorphisms in the coding region of the GCH-I gene were identified. None of the mutations of GCH-I gene in HPD reported to date or in this study have been detected more than once in any ethnicity suggesting a relatively high spontaneous mutation rate in this gene.     

Cholinergic inputs to rostral ventrolateral medulla pressor neurons from hypothalamus

The rostral ventrolateral medulla (RVLM) has cholinergic mechanisms responsible for pressor responses. Stimulation of the hypothalamic paraventricular nucleus (PVN) causes an increase of arterial pressure via activation of neurons in the RVLM. In this study, we examined whether PVN stimulation causes a pressor response via activation of cholinergic mechanisms in the RVLM. Male Wistar rats were used and they were anesthetized, paralyzed and artificially ventilated. Electrical stimulation of the PVN produced a pressor response. Microinjection of the muscarinic receptor antagonist scopolamine and the cholinesterase inhibitor physostigmine into the RVLM inhibited and potentiated, respectively, the pressor response induced by PVN stimulation. PVN stimulation also increased the firing rate of RVLM barosensitive neurons and the increase in the firing rate was inhibited and potentiated by scopolamine and physostigmine, respectively, iontophoretically applied on neurons. Microinjection of L-glutamate into the PVN produced a release of ACh in the RVLM. The inhibitory amino acid gamma-aminobutyric acid injected into the lateral parabrachial nucleus (LPBN) inhibited the pressor response induced by PVN stimulation. These results suggest that PVN stimulation causes an increase in arterial pressure via activation of cholinergic inputs in the RVLM. It appears that the pressor response is mediated, at least in part, via cholinergic inputs from the LPBN.     

Norepinephrine‐induced diastolic dysfunction with aortic valve opening under calcium‐loading in rats

Heart failure associated with a high plasma level of norepinephrine (NE) has an extremely poor prognosis with NE being the most powerful predictor of all‐cause mortality. An increase in the diastolic intracellular calcium level (Ca²⁺) occurs in left ventricular dysfunction; however, the cause‐and‐effect relationships among Ca²⁺loading, high plasma NE, and an increase in diastolic ventricular pressure is unclear. Here, we examined the relationship between diastolic dysfunction and NE with and without Ca²⁺loading in rats. Animals were studied in four groups: Ca²⁺loading for 45 min (Ca²⁺group), NE alone for 25 min (30 µg/kg/min NE for 25 min; NE group), Ca²⁺loading and NE for 25 min after Ca²⁺loading (Ca²⁺‐NE group), and a vehicle group. Hemodynamics were examined using a micromanometer‐tipped pressure catheter, and diastolic function was studied using Doppler echocardiography. Significantly increased left ventricular end‐diastolic pressure (LVEDP) and decreased E and Ea waves and deceleration time (DCT) were found in the Ca²⁺‐NE group, compared with the Ca²⁺and NE groups. There were no changes in left ventricular pressure (LVP) and LV ejection fraction (EF) among the four groups. NE‐induced diastolic contracture (NEIDC) with aortic valve opening occurred in the diastole when LVP overshot the aortic pressure after co‐administration of NE and Ca²⁺after Ca²⁺loading, and pulmonary hemorrhage was observed in all animals of the Ca²⁺‐NE group. The results support the suggestion that NE may be an important factor in the development of diastolic dysfunction in ischemic heart disease. Drug Dev. Res. 67:511–518, 2006. © 2006 Wiley‐Liss, Inc.     

K201 Improves norepinephrine‐induced diastolic dysfunction with preserved ejection fraction

Heart failure with preserved ejection fraction differs from systolic heart failure in pathogenesis, underlying disease, and prognosis; however, the onset mechanism of this type of heart failure remains unknown and there is no proven therapy. Recently, we showed that norepinephrine (NE) under Ca²⁺ loading induces severe diastolic dysfunction without a significant change in the left ventricular ejection fraction (LVEF), that is, increased left ventricular end‐diastolic pressure (LVEDP), norepinephrine‐induced diastolic contracture (NEIDC), and diastolic opening of the aortic valve. In this study, the effects of two benzothiazepine derivatives, K201 (JTV519) and diltiazem, on diastolic dysfunction were examined using this model. K201 significantly suppressed the increase in LVEDP, reduced the incidence of NEIDC, and significantly improved the Ea wave and DCT in a dose‐dependent manner, as well as reducing pulmonary hemorrhage. In contrast, diltiazem did not improve diastolic dysfunction and the mortality in the diltiazem group was 57%, compared to 0% in the K201 group. These results suggest that reduction of intracellular Ca²⁺ alone does not inhibit diastolic heart failure; in contrast, blocking of α‐adrenoceptors and regulation of proteins such as troponin I via protein kinase C are required for treatment of diastolic heart failure. These results also suggest that K201 may be an agent for treatment of diastolic heart failure. Drug Dev. Res. 67:852–861, 2006. © 2007 Wiley‐Liss, Inc.     

Abnormal vestibular evoked myogenic potentials in the presence of normal caloric responses.

OBJECTIVE: Combined use of vestibular evoked myogenic potential (VEMP) and caloric response testing has enabled us to examine the function of the inferior and superior vestibular nerves separately. Although results of VEMP testing and caloric response testing have been reported for many diseases, a clinical entity showing abnormal VEMP responses but normal caloric test responses has rarely been reported. The aim of the study was to investigate clinical features of diseases showing abnormal VEMP responses with normal caloric test responses. STUDY DESIGN: Retrospective. SETTING: University hospital. PATIENTS: Eight hundred eleven patients with balance problems who had undergone both caloric response and VEMP testing were included in the study. MAIN OUTCOME MEASURES: The amplitudes and latencies of the first positive-negative peak of the VEMP (p13-n23) were measured. RESULTS: Forty of the 811 patients (5%) were found to have abnormal VEMP responses with normal caloric test responses. Clinical diagnoses of these patients were Ménière's disease (n = 12), acoustic neuroma (n = 8), sudden deafness with vertigo (n = 6), and other diseases (n = 6). Eight patients could not be diagnosed as having a disease already recognized. Clinical manifestations of these eight patients were rotatory vertigo in six patients and non-rotatory dizziness in two. None of these patients showed abnormalities other than VEMP responses on neurologic or neurotologic examinations. CONCLUSION: Apart from Ménière's disease, acoustic neuroma, and sudden deafness with vertigo, which are already known as diseases with abnormal VEMP responses but normal caloric test responses, some patients might be diagnosed as having a disease that involves only the inferior vestibular nerve region.     

Nuclear FABP7 immunoreactivity is preferentially expressed in infiltrative glioma and is associated with poor prognosis in EGFR-overexpressing glioblastoma

Background  

We previously identified brain type fatty acid-binding protein (FABP7) as a prognostic marker for patients with glioblastoma (GBM). Increased expression of FABP7 is associated with reduced survival. To investigate possible molecular mechanisms underlying this association, we compared the expression and subcellular localization of FABP7 in non-tumor brain tissues with different types of glioma, and examined the expression of FABP7 and epidermal growth factor receptor (EGFR) in GBM tumors.     

Changes in left ventricular end-diastolic area, end-systolic wall stress, and fractional area change during anesthetic induction with propofol or thiamylal

Purpose. To elucidate the mechanisms of the more profound hypotensive effects of propofol relative to thiamylal, we monitored changes in left ventricular (LV) preload, afterload, and contractility during the course of anesthetic induction with propofol and thiamylal. Methods. Thirty-two patients (ASA I) were randomly assigned into two groups and injected with propofol (2 mg·kg⁻¹) or thiamylal (4 mg·kg⁻¹) as anesthetic induction agents. Transthoracic echocardiography (TTE) was used to assess LV performance before and during induction by the two anesthetics. The LV end-diastolic area (EDA) and LV end-systolic wall stress (ESWS) were used as indices of LV preload and LV afterload, respectively, while LV contractility was assessed by the fractional area change (FAC). Results. Both propofol and thiamylal significantly reduced EDA and ESWS without significant change in FAC. Propofol-induced reductions in EDA and ESWS were significantly greater than those of thiamylal. Conclusion. The more profound hypotension observed during induction of anesthesia with propofol is due to the greater decrease in preload and afterload than with thiamylal, but not to a decrease in LV contractility. Received: December 8, 1999 / Accepted: April 19, 2000     

Plasminogen activator inhibitor-1 in girls with precocious pubarche: a premenarcheal marker for polycystic ovary syndrome?

In both obese and nonobese women, polycystic ovary syndrome (PCOS) is essentially a disorder of hyperinsulinemic insulin resistance, and it may be heralded by precocious pubarche (PP; appearance of pubic hair in girls aged <8 y). The risk of progression from PP to PCOS is related to low birth weight, but there are no early biochemical markers of this risk. As increased plasminogen activator-inhibitor type 1 (PAI-1) activity (act) is an early marker of cardiovascular risk in PCOS, we have sought abnormalities in young girls with PP. In 33 young PP girls (age range 6-11 y), PAI-1-act was increased (mean + SEM: 15.6 +/- 1.5 IU/mL) compared with age-, sex-, and pubertal stage-matched controls (n = 13, 10.7 +/- 1.9, p < 0.05). PAI-1-act levels were inversely related to birth weight SD score (r = -0.33, p < 0.05), and PAI-1-act levels were therefore higher in PP girls with low birth weights (n = 14, 19.5 +/- 2.5 IU/mL) than normal birth weights (n = 19, 12.8 +/- 1.5, p < 0.01). During longitudinal observation in 10 PP girls (mean time interval 2.7 y), PAI-1-act levels in early puberty were positively related to postmenarcheal insulin levels (mean serum insulin SDS postoral glucose, r = 0.65, p < 0.05), and showed a similar relationship to postmenarcheal testosterone levels (r = 0.61, p = 0.06). Together with low birth weight, increased plasma PAI-1-act levels in early pubertal PP girls may indicate those girls with greater risk of developing hyperinsulinemic-hyperandrogenism features of PCOS.